While the importance of osteoporosis as a major, and growing, public health problem is now well recognized, there remain significant gaps in our clinical and basic understanding of this disorder. Thus, the overall goal of this Program Project Grant (PPG) is to better define the pathogenesis and population impact of age-related bone loss and fractures. As in the past, the major strength of our group is to bring together diverse disciplines into synergistic interactions, and the present application includes clinical-investigatve studies in the Clinical Research Unit (CRU) in Project 1, population-based epidemiology studies in Project 2, and basic mouse/cellular studies in Project 3. The three Projects are supported by an Administrative and Biostatistics Core. Although the approaches being used in each of the Projects differ, the central theme of this PPG, which is addressed by Aim 1 of each Project, is to better understand the role of the sympathetic nervous system (SNS) in regulating bone metabolism and age-related bone loss. Thus, the effects of increased sympathetic outflow in contributing to impaired bone formation and increased bone resorption with aging in estrogen (E)- deficient postmenopausal women are addressed by Aim 1 of Project 1, whereas the population impact of an important age-related clinical condition associated with increased sympathetic outflow, heart failure (HF), will be studied in Aim 1 of Project 2. Similarly, Aim 1 of Project 3 will use mouse models to examine potential interactions between SNS and E signaling in bone. Subsequent Aims of each Project remain closely related to the first Aim, but address more Project-specific issues relevant to age-related bone loss and fractures. Thus, Project 1 will also identify other, fundamental mechanisms responsible for the age-related impairment in bone formation. For the latter studies, we will utilize novel techniques developed in our laboratory to isolate highly enriched populations of osteoblasts and osteocytes from human needle bone biopsies and analyzed without the need for in vitro culture. Project 2 will enhance fracture risk assessment and identify clinically relevant pathophysiologic mechanisms from a population-based perspective. Thus, in addition to evaluating the impact of HF on fracture risk, these studies will address the major unresolved issue of how emerging comorbid conditions interact to determine fracture risk with aging. Project 3 will employ mouse models to examine potential interactions between SNS and E signaling in bone. These studies will also fill important gaps in knowledge regarding E regulation of bone turnover by using conditional deletion of estrogen receptors [ERs] and in adult mice, thereby differentiating the role of these receptors in skeleta development versus in regulation of the adult skeleton. The Core will provide administrative leadership, critical infrastructure, and the biostatistical and bioinformatics resources needed for the three Projects.